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Author afliations appear just before the reference list at the end of the article.
ABSTRACT
This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence,
pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management
based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of
bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%),
where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is
estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the
pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and
macrophage function, as well as the role of local bacterial infection, inammation, and necrosis. Advances in imaging include the use
of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic
resonance imaging, bone scanning, and positron emission tomography, although plain lms often sufce. Other risk factors for ONJ
include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inammation, diabetes mellitus, ill-
tting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or
stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients
at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be
given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal
coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy
and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical
debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous
wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell
intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue
grafting. 2014 American Society for Bone and Mineral Research.
KEY WORDS: OSTEONECROSIS OF THE JAW; BISPHOSPHONATES; DENOSUMAB; IMAGING; RISK FACTORS; DIAGNOSIS; TREATMENT;
MANAGEMENT
Received in original form August 26, 2014; revised form November 3, 2014; accepted November 5, 2014. Accepted manuscript online November 21, 2014.
Address correspondence to: Aliya A. Khan, #209-331 Sheddon Avenue, Oakville, Ontario, Canada. E-mail: aliya@mcmaster.ca
Additional supporting information may be found in the online version of this article.
Journal of Bone and Mineral Research, Vol. 30, No. 1, January 2015, pp 323
DOI: 10.1002/jbmr.2405
2014 American Society for Bone and Mineral Research
3
provider, in a patient who was receiving or had been exposed International Association of Oral and Maxillofacial Surgeons,
to a BP and who has not received radiation therapy to the International Society of Oral Oncology, Japanese Society for
craniofacial region.(3) The American Association of Oral and Bone and Mineral Research, Osteoporosis Canada, Pan Arab
Maxillofacial Surgeons (AAOMS) has recently (2014) updated Osteoporosis Society and The Endocrine Society). The Task Force
their denition of medication-related ONJ to (1) current or formalized nine key questions to be addressed relevant to the
previous treatment with antiresorptive or antiangiogenic diagnosis and management of ONJ in oncology and osteoporo-
agents; (2) exposed bone or bone that can be probed through sis patient populations (Supporting Table S1). A systematic
an intraoral or extraoral stula(e) in the maxillofacial region review of published literature was completed based on these
that has persisted for more than 8 weeks; and (3) no history of key questions. A search strategy was developed by combining
radiation therapy to the jaws or obvious metastatic disease to medical subject headings and/or text words from four
the jaws.(4) categories: interventions (BPs and denosumab); population
The International Task Force on Osteonecrosis of the Jaw (oncology and osteoporosis); areas of interest for the review
(hereafter, this Task Force or the Task Force) denes ONJ as: (1) (classication, diagnosis, incidence, risk factors, treatment); and
exposed bone in the maxillofacial region that does not heal outcome (osteonecrosis of the jaw). All searches were limited to
within 8 weeks after identication by a health care provider; (2) human studies published in the English language and excluded
exposure to an antiresorptive agent; and (3) no history of reviews, editorials, and letters. The electronic search was
radiation therapy to the craniofacial region. Early data suggest conducted in Medline (January 1, 2003 to April 10, 2014) and
that antiangiogenic agents may contribute to the development EMBASE (January 1, 2003 to April 10, 2014) using OVID (see
of ONJ in the absence of concomitant BP therapy; the Task Force Supporting Table S2 for search strategies). The results from both
plans to address this in more detail in a subsequent document as databases were combined and duplicates excluded. The
more evidence emerges. Cochrane Database of systematic reviews was also searched
for applicable references. A manual search of the bibliography of
Oral ulceration with bone sequestration identied published articles was also performed. In order to
obtain additional unpublished data, personal communication
The Task Force is also of the view that bone necrosis may with relevant experts was conducted and pharmaceutical
occur in the absence of antiresorptive therapy, with companies were invited to submit relevant information. A total
attendant oral ulceration and bone sequestration (OUBS). of 46 records were included from manual searches and expert
However, such occurrences, typically associated with signi- communication. The total number of references were reviewed
cant morbidity, are uncommon. OUBS was initially described was 933 and from these, 599 papers were reviewed in full (see
as lingual mandibular sequestration and ulceration because Supporting Fig. S1 for articles reviewed and retained for each of
of the predilection for involvement of the posterior lingual the nine questions).
mandibular bone, but this terminology has been replaced by The published literature was critically appraised and graded
OUBS. The sequestrum can slough spontaneously, resulting in based on quality of evidence (see Supporting Table S3 for
rapid resolution. However, in some cases, conservative Level of Evidence scales and Supporting Tables S4 and S5 for
surgical removal of the dead bone is indicated to permit Evidence Grades, respectively). All assessments were made in
efcient healing.(57) The incidence of OUBS in the general duplicate with disagreements discussed between reviewers
population is not well dened. It is possible that cases of until consensus was achieved. If no consensus was possible, a
OUBS may be captured in incidence data pertaining to drug- third reviewer would have provided the nal decision.
related ONJ. Currently, it is not known what proportion of the However, adjudication by a third reviewer was not necessary
spontaneous sequestration cases persist beyond 8 weeks and in any instance.
there are no studies identifying the prevalence or incidence The key questions and a summary of the current evidence
of OUBS. OUBS was not included in the main systematic were reviewed in detail by the ONJ Task Force at an in-
review, which pertains to drug-related ONJ; however, this person meeting in October 2012. The panel members were
Task Force conducted a separate literature search on OUBS divided into subgroups, with each subgroup being respon-
and, at the end of this document, has provided a summary of sible for responding to a specic question, each represented
that search as well as current recommendations pertaining in a section of this systematic review. Each subgroup
to diagnosis and management based on international communicated electronically, and regularly scheduled con-
consensus. ference calls were implemented in order to address points of
controversy in order to arrive at consensus. The co-chairs
reviewed the sections from each of the subgroups and
Methods completed the manuscript. The manuscript was circulated to
the Task Force and was modied until consensus was
In January 2012, an International ONJ Task Force was formed achieved on each of the sections; there were a total of 21
with expertise from basic science and from multiple medical, circulations and manuscript revisions. A second in-person
dental, and surgical specialties. There was representation from meeting occurred in October 2013, followed by teleconfer-
14 national and international societies addressing bone health ences to ensure that all recommendations had consensus
(The sponsoring societies are the American Society of Bone and agreement. Consensus was not achieved regarding appro-
Mineral Research, American Association of Oral and Maxillofacial priate terminology for staging of ONJ because of limited
Surgeons, Canadian Association of Oral and Maxillofacial available prospective data. After approval by each of the
Surgeons, Canadian Academy of Oral and Maxillofacial Patholo- supporting societies, the manuscript was nalized. Funding
gy and Oral Medicine, European Calcied Tissue Society, and in-kind support for the ONJ Task Force has been received
International Bone and Mineral Society, International Society solely from the sponsoring societies; industry support was
of Clinical Densitometry, International Osteoporosis Foundation, not requested nor received.
Journal of Bone and Mineral Research OSTEONECROSIS OF THE JAW: REPORT FROM THE INTERNATIONAL ONJ TASK FORCE 5
therapy will present to the dentists ofce for common dental prevalence rates of 0% to 0.348% and the majority being under
care. Overdiagnosing patients with ONJ could lead to detrimen- 0.005%.(47,48,5860) Felsenberg(61) noted a prevalence of ONJ in
tal effects in their skeletal health, especially if modication or patients treated with BPs for osteoporosis of <1/100,000. Lo and
discontinuation of the antiresorptive medication is entertained. colleagues(52) evaluated the Kaiser Permanente database and
Odontalgia is caused by a number of conditions, necessitating found the prevalence of ONJ in those receiving BPs for more
careful exclusion. Radiographic ndings of altered bone than 2 years to range from 0.05% to 0.21% and appeared to be
morphology, increased bone density, sequestration, or perios- related to duration of exposure. In Canada, Khan and
teal bone formation in a patient with odontalgia may be early colleagues(62) completed a survey of oral surgeons in Ontario
radiographic features suggestive of a prodromal phase of ONJ and found the prevalence of ONJ in those on BPs to be
and such patients require close follow-up and monitoring by the approximately 0.001%.
oral health care provider (see Supporting Table S8). It appears Barasch and colleagues(24) completed a case-control study and
from the limited data available that up to 50% of such patients noted an association between oral BPs and ONJ with an odds ratio
may progress to the development of clinical ONJ with bone (OR) of 12.2 (95% condence interval [CI], 4.3 to 35). This study,
exposure.(19) Several members of the Task Force felt that this however, included patients with cancer on oncologic doses of
condition could be referred to as preclinical ONJ. However, BPs, which likely increased the incidence of ONJ. Vestergaard and
because at least 50% of these lesions do not progress to overt colleagues(63) evaluated jaw-related events in BP users with
ONJ, the Task Force felt unable to unanimously support the nonusers in a historical cohort study and noted a hazard ratio (HR)
designation preclinical ONJ as appropriate for this particular of 3.15 (95% CI, 1.44 to 6.87) with alendronate use.
clinical manifestation until further prospective data become
available.
Incidence
ONJ lesions occur more commonly in the mandible than the
maxilla (65% mandible, 28.4% maxilla, 6.5% both mandible and The incidence of ONJ in patients prescribed oral BPs for the
maxilla, and 0.1% other locations; see Supporting Table A2) and treatment of osteoporosis ranges from 1.04 to 69 per 100,000
are also more prevalent in areas with thin mucosa overlying patient-years.(62,6466) The incidence of ONJ in patients
bone prominences such as tori, exostoses, and the mylohyoid prescribed i.v. BPs for the treatment of ONJ ranges from 0
ridge.(9,32,35) The extent of lesions can vary and range from a to 90 per 100,000 patient-years.(58,59,65,67,68) Last, the incidence
nonhealing extraction site to exposure and necrosis of large of ONJ in patients who are prescribed Dmab ranges from 0 to
sections of the mandible or maxilla.(18) The exposed bone is 30.2 per 100,000 patient-years.(6972) In Australia, Mavrokokki
typically surrounded by inamed erythematous soft tissue. and colleagues(54) conducted a national survey and found the
Purulent discharge at the site of the exposed bone is evident in incidence of ONJ in osteoporotic patients receiving BPs to be
the presence of secondary infection.(36,37) Microbial cultures 0.01% to 0.04%. However, in Sweden, Ulmner and col-
from areas of exposed bone usually isolate normal oral leagues(66) surveyed oral surgery and dental clinics and
microbes.(38,39) However, in the presence of extensive soft estimated an incidence of 0.067%. Zavras and Zhu(73)
tissue involvement, microbial cultures may identify coexisting evaluated medical claims in the United States and found no
oral pathogens and enable the selection of an appropriate association between oral BP use and the risk of minor jaw
antibiotic regimen. Interestingly, although ONJ is exclusive to surgery. However, in those receiving i.v. BPs there was a
the jaws by denition, it should be noted that osteonecrosis of fourfold increased risk of minor jaw surgery, possibly reecting
the external auditory canal in patients on BP therapy has also an increased risk of ONJ. Similar ndings were noted by
been reported.(4046) Pazianas and colleagues.(74)
In the Health Outcomes and Reduced Incidence with
2. How common is ONJ? Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial
involving 7765 patients receiving either zoledronic acid 5 mg or
For the full review of evidence regarding the prevalence and
placebo over 3 years, a single adjudicated case of ONJ was
incidence of ONJ in osteoporotic and oncology populations,
identied in each arm. Both patients had additional risk factors
please refer to Supporting Tables A3 and A4, respectively.
for ONJ (prednisone use in the patient receiving placebo and
2a. Osteoporosis diabetes with dental abscess in the patient receiving zoledronic
acid) and both resolved with antibiotics and debridement.(67)
There are very limited prospective cohort data evaluating the The data from four additional randomized controlled trials
frequency of ONJ in the osteoporosis patient population, (RCTs) evaluating 5 mg zoledronic acid were combined with the
making it difcult to accurately evaluate its incidence. The data from the HORIZON Pivotal Fracture Trial and the overall
published data evaluating the incidence of ONJ have largely incidence of ONJ was reviewed.(75) The additional trials included:
been obtained from case-series, retrospective observational the HORIZON Recurrent Fracture Trial with 2127 subjects after a
studies, or retrospective cohort studies, typically from pooled recent low-trauma hip fracture followed for 1.9 years(58); the
data from insurance or healthcare databases. Pooled data can be Glucocorticoid-Induced Osteoporosis Trial involved 833 subjects
problematic in that search terms may not be specic to ONJ. and compared zoledronic acid 5 mg or risedronate 5 mg over 1
year(76); the Male Osteoporosis Trial involved 302 subjects
followed over 2 years receiving either zoledronic acid 5 mg
Prevalence
annually or alendronate 70 mg orally weekly(77); and the
The prevalence of ONJ in patients prescribed oral BPs for the Prevention of Osteoporosis Trial evaluated 581 subjects over
treatment of osteoporosis ranges from 0% to 0.04%, with the 2 years randomized to either zoledronic acid 5 mg annually
majority being below 0.001%.(4757) The prevalence of ONJ in versus placebo.(78) The combined adverse event database was
those prescribed high dose intravenous (i.v.) BPs is signicantly searched for possible cases of ONJ using preferred Medical
higher than that seen with low dose i.v. or oral BPs, with Dictionary for Regulatory Activities terms and no additional
Journal of Bone and Mineral Research OSTEONECROSIS OF THE JAW: REPORT FROM THE INTERNATIONAL ONJ TASK FORCE 7
Epidemiological data on the prevalence and incidence of ONJ Bone turnover
are limited and, when available, typically not based on
Suppression of bone turnover may also play a role in the
prospective studies or population-based surveys.
development of ONJ.(180,181) The association of ONJ with potent
Signicant risk factors for the development of ONJ in the
antiresorptive drugs(62,69) and the increased risk with higher
oncology population, in declining order of importance, include:
doses of BPs and Dmab would be consistent with this
i.v. BPs (both dose of BP and duration of exposure impact ONJ
contention.(14,62,120) In Beagle dogs treated with high doses of
risk)(24); zoledronic acid(83,105,112,150,164); pamidronate(150); Dmab
BPs, areas of necrosis in the mandible sometimes develop, with
(from incidence and prevalence data); radiation therapy(24);
nonviable osteocytes in the affected bone.(15) However, low
dental extraction(24,105,150,161,165); chemotherapy(84); periodontal
bone turnover is not characteristically seen in affected tissue
disease(166); oral BP use(24); osteoporosis(105); local suppura-
from ONJ patients(166); furthermore, ONJ has not been reported
tion(24); glucocorticoid therapy(106); diabetes(28); denture
in other conditions associated with low bone turnover.
use(150,165,167); erythropoietin therapy(106); tobacco use(28);
hyperthyroidism(28); renal dialysis(106); cyclophosphamide ther-
apy(106); etidronate(168); and increasing age.(106,161) Vascularity
Signicant risk factors for the development of ONJ in the
BPs are known to have antiangiogenic properties(177179) and it
osteoporosis patient population, in declining order of impor-
has been suggested that these may also contribute to the
tance, include: suppuration(24); BP use(24); dental extraction(24);
development of ONJ. ONJ has been described in several patients
and anemia.(24)
treated for cancer with antiangiogenic agents, in particular
Although Dmab was not identied as a risk factor in any of the
sunitinib(182) and bevacizumab,(157) although in these patients
searches, the data presented in the incidence and prevalence
other risk factors were also present. Dmab is not known to have
section would suggest that it is an additional risk factor, similar
antiangiogenic effects, and normal vasculature has been
to BPs. It should be noted that both the BPs and Dmab are
reported in most histological studies of ONJ tissue.(166,183)
essentially included in the denition of drug-associated ONJ, so
Animal studies with BPs do not support any diminution of
dening either as a risk factor for drug-related ONJ is
vascular volume with BP administration.(184)
methodologically perilous. However, it is clear that both of
these drugs increase the incidence and prevalence of ONJ in
both osteoporotic and oncology populations, as described in Genetic predisposition
section 2 (How common is ONJ?), and are thus strongly
Not all patients with similar comorbidities and similar medical
implicated as being risk factors for ONJ.
management develop ONJ; hence, pharmacogenomics may
inuence the risk of developing ONJ. It has been suggested that
4. Why does ONJ develop? polymorphisms in the farnesyl pyrophosphate synthase(185) or
The pathophysiology of ONJ is not well understood. Until cytochrome P450 CYP2C8 genes(186,187) might predispose some
recently, most studies addressed the potential role of BPs, but individuals to develop ONJ. Genomewide association case-
the knowledge that Dmab therapy also increases the risk of control studies have been performed in oncology patients and
ONJ(13,69) emphasizes the need to explore mechanisms this is an area undergoing further exploration.(188,189)
common to both interventions. All of the evidence reviewed
regarding the pathophysiology/etiology of ONJ is provided in 5. What is the role of imaging in diagnosis and
Supporting Table A6. A summary of these data is provided in management?
Supporting Table S10.
The evidence reviewed for the imaging of ONJ can be found in
Supporting Table A7.
ONJ is a clinical diagnosis based on history and physical
Infection
exam. Radiographic features of ONJ remain relatively nonspe-
The sequence of events leading to the development of ONJ cic. Plain lm radiography is usually unremarkable in the early
is unclear; in particular, it is unknown whether necrosis stages of the disease because decalcication is limited.(190) The
precedes or follows infection. Dental disease is a well- presence of localized or diffuse osteosclerosis or a thickening
established risk factor for ONJ,(35) implicating infection and of the lamina dura on plain lm imaging may predict future
inammation in the pathogenetic process. Aggregates of sites of exposed necrotic bone.(190) Poor ossication at a
bacteria and polymorphonuclear leukocytes are commonly previous extraction site may also be an early radiographic
seen in ONJ tissue and the presence of bacterial microlms feature of ONJ. Findings on computed tomography (CT) are
has been described in close association with active nonspecic and may include areas of focal sclerosis, thickened
osteoclastic resorption on the bone surface.(38,166) Bacteria lamina dura, early sequestrum formation, and reactive
are known to stimulate bone resorption(169,170); hence, the periosteal bone.(191194) CT imaging is of value in delineating
microorganisms present may directly contribute to bone the extent of disease and is helpful in planning surgical
necrosis. In addition to preexisting dental trauma and intervention.(192,195) Features noted on bone scanning include
disease, inhibitory effects of BPs on the proliferation and increased tracer uptake at sites that subsequently develop
viability of oral keratinocytes(171176) may further damage necrosis.(196) The utility of nuclear bone scanning in patients at
the integrity of the oral mucosa and increase the risk of risk of ONJ requires further study.(196,197)
infection. Activation by BPs of gamma delta T cells may Imaging modalities used as adjunctive assessment in the
stimulate the production of proinammatory cytokines and evaluation of the ONJ patient may include plain radiographs, CT,
later depletion of these T cells may impair the immune magnetic resonance imaging (MRI), and functional imaging with
response to infection.(177179) bone scintigraphy and positron emission tomography (PET).
Journal of Bone and Mineral Research OSTEONECROSIS OF THE JAW: REPORT FROM THE INTERNATIONAL ONJ TASK FORCE 9
In summary, imaging is of value in diagnosing ONJ. This is ONJ is a complication associated with the use of the
particularly the case in those individuals on antiresorptive antiresorptive therapies, either with BPs and/or Dmab. Marx
therapy with ONJ-like symptoms, but without obvious bone and colleagues(227) suggested that quantication of bone
exposure. Because periapical and periodontal disease is an resorption may be useful for prognosis. They reported data
important risk factor for ONJ, identifying early dental disease on 30 women treated with oral BPs for low bone density who
with imaging and proceeding with dental preventive measures had subsequently presented with ONJ. Seventeen of these
may decrease the risk of ONJ and minimize the need for dental women were still taking oral BP at the time of presentation, and
extractions.(118,219) In addition, imaging enables exclusion of had C-terminal telopeptide (CTX) values of 30 to 102 pg/mL
other conditions that may contribute to necrosis, such as (mean 73 pg/mL). After 6 months off BPs, CTX values were 162 to
metastatic disease.(220,221) There are no pathognomonic features 343 pg/mL (mean 228 pg/mL), a mean rise of 26 pg/mL/month.
of ONJ on imaging that denitively differentiate ONJ from other ONJ healed in all patients over the following 18 months, and the
conditions.(222) However, imaging can assist in identifying the authors concluded that this was causally associated with the
extent of bone and soft tissue disease as well as providing higher bone turnover. Although this is possible, the hypothesis
information on dental, periodontal, and periapical health. A was not formally tested because none of the patients were
summary of imaging ndings with ONJ is presented in assessed while continuing BP therapy. At presentation, there
Supporting Table S11. was no correlation between CTX and clinical severity in this
cohort, nor in 60 other ONJ patients receiving i.v. BPs. They
concluded that if CTX is >150 pg/mL in patients receiving oral
Recommendations for imaging
BPs then invasive oral surgical procedures can be completed
A. Individuals on low-dose antiresorptive treatment without with minimal risk of osteonecrosis, although no data supporting
signs or symptoms of ONJ do not require any additional imaging this statement are presented (Marx criteria: CTX <100 pg/
over and above routine dental evaluation.(223225) mL high risk, 100 to 150 pg/mL moderate risk, and >150 pg/
B. Patients on high-dose antiresorptive treatment without mL minimal risk).
ONJ are at signicant risk of developing ONJ and early Cross-sectional studies in patients with ONJ have evaluated
identication of dental disease is important.(118,219) Following the association between CTX levels and disease severity.
a complete examination of the oral cavity, high-risk patients Although Bagan and colleagues(228) found no relationship in
should ideally receive bitewing and periapical intraoral radio- 15 oncology patients, Kwon and colleagues(229) found that CTX
graphs of all existing teeth as well as panoramic radiographs. levels were related (r 0.47) to the number of the ONJ lesions
When available, CBCT 3D imaging using high-resolution and their stage in 18 patients receiving oral BP therapy, although
protocols could also be performed, given the superior ability CTX levels were not different from those in BP-treated
of CBCT (compared to conventional radiographs) in diagnosing osteoporosis patients without ONJ.(230)
periapical and periodontal disease. Following a baseline The utility of CTX has been evaluated in its ability to predict
evaluation of oral health, additional conventional and CBCT outcomes in patients with ONJ. In each of these studies, many
radiographs are performed only if necessary in the presence of patients were at risk by the Marx criteria. Atalay and
oral complaints or signs or symptoms of ONJ.(226) colleagues(231) found that CTX did not predict treatment
C. In patients in whom ONJ is a clinical consideration on low- prognosis in 20 cancer patients, despite a wide range of
dose or high-dose antiresorptive therapy presenting with oral baseline CTX values. CTX levels in BP-treated subjects have been
symptoms, CBCT or CT imaging may aid in evaluating early assessed as a predictor of ONJ risk after oral surgery. Kunchur
changes in the cortical and trabecular architecture of the maxilla and colleagues(232) measured CTX in 222 BP users undergoing
and mandible. Imaging also allows assessment of possible extractions. Only one patient developed ONJ and had a
sequestrum or stula track formation and evaluation of the moderate level of CTX (126 pg/mL). Lee and Suzuki(233) assessed
status of any involved teeth. If both CBCT and CT are available, CTX levels in 54 patients on oral BPs undergoing oral surgery and
small-FOV, high-resolution CBCT is preferred because it delivers despite a very wide range of CTX values prior to surgery (39 to
less radiation and provides similar diagnostic information as CT. 330 pg/mL; mean of 161 pg/mL), no patient developed ONJ.
CBCT may be performed in conjunction with bitewing, Similarly, OConnell and colleagues(234) measured CTX values in
periapical, and panoramic radiographs. If clinically indicated, 23 patients on BPs, 21 with osteoporosis and two with cancer,
MRI may provide additional information of the presence and prior to oral surgery (CTX range, 50 to 370 pg/mL; mean 180 pg/
extent of osteonecrosis. mL). After 5 months of observation, no patient had developed
D. In patients with clinical ONJ under conservative manage- ONJ. In the HORIZON trial, one case of ONJ developed in 5903
ment (Stage 1 and 2), the nature and extent of osseous changes patients given zoledronic acid, and a second case developed in
around the area of clinical bone exposure can be evaluated with the 5140 placebo-treated subjects.(75) In this trial, 43% of
CT or small-FOV high-resolution CBCT imaging. Dental disease in patients had serum CTX <100 ng/mL 6 months after zoledronic
all existing teeth should also be determined with bitewing, acid and would be considered at high risk by the Marx criteria,
periapical, and panoramic radiographs. yet ONJ risk was no higher than in the placebo group. The very
E. In patients with clinical ONJ where surgical intervention is low incidence of ONJ in osteoporosis subjects indicates that
considered (Stage 2 and 3), CBCT or CT may be complemented even very large studies are underpowered to answer this
with MRI, bone scan, or PET for a more thorough evaluation of question.
involved bone and soft tissues. Few other biomarkers of bone turnover have been assessed
with respect to ONJ management or to their utility in making
6. Are biomarkers useful in identifying ONJ? decisions regarding the individual patients risk for ONJ. One
study found that neither N-terminal telopeptide (NTX) nor bone
Please refer to Supporting Table A8 for a full description of all the alkaline phosphatase was associated with the development of
papers reviewed in this section. ONJ.(235) Lehrer and colleagues(236,237) performed two studies
Journal of Bone and Mineral Research OSTEONECROSIS OF THE JAW: REPORT FROM THE INTERNATIONAL ONJ TASK FORCE 11
the American Dental Association,(1,2,33,245) and is supported by We propose that if surgery is indicated, resection with
many practitioners.(132,246) Conservative therapy is the mainstay tension-free closure affords the most positive results.
of care and although it may not necessarily lead to complete Adjunctive treatments, in combination with surgery, have
resolution of lesions, it may symptomatically provide long-term been also described in the literature. Vescovi and col-
relief.(26,247) Among patients with breast cancer and multiple leagues(262) achieved good results treating ONJ lesions with
myeloma, Fortuna and colleagues(248) reported a more rapid laser-assisted surgical debridement; in contrast, Atalay and
response to conservative therapy in the breast cancer group colleagues(231) found no statistically signicant benet of this
compared to those with multiple myeloma. approach in comparison to conventional surgery. Martins and
Recent case reports of successful treatment of ONJ with colleagues(266) conducted a preliminary retrospective survey
teriparatide are encouraging(249,250) and this may become a of patients undergoing antibiotic therapy plus surgery
conservative treatment choice for those with osteoporosis and followed by low-level laser therapy and platelet-rich plasma
without cancer or prior radiation therapy to bone. Because applied to the surgical wound, and observed improved
teriparatide has been reported to facilitate osseous wound healing.
healing in the oral cavity,(249) it may be a viable approach for Promising results have also been reported with surgical
patients on antiresorptive therapy for the treatment of debridement in combination with platelet-derived growth
osteoporosis. Considering the low risk of ONJ in patients with factor (PDGF) applied to the site in Stage 2 ONJ cases.(242)
osteoporosis being treated with osteoporosis doses of anti- Pautke and colleagues(267) reported that intraoperative uores-
resorptive agents and the absence of evidence that changing to cence guidance was helpful in identifying surgical resection
teriparatide would alter the outcome of an invasive dental margins in Stage 2 ONJ cases. Hoefert and Eunger(268)
procedure in someone who does not have ONJ, it is not suggested that longer-term preoperative antibiotics (23 to 54
recommended at this time to switch to teriparatide in those at a days) resulted in improved surgical outcomes versus short-term
low risk of ONJ or fracture. However, in an osteoporotic patient antibiotic therapy (1 to 8 days). Surgical success rates have been
with established ONJ, treatment with teriparatide may be of higher in patients with multiple myeloma or in those with
value as observed in published case reports.(251256) osteoporosis receiving low-dose BP therapy in comparison to
The same approach should not be used in patients with patients with solid tumors.(269)
cancer, a history of skeletal radiation, or with active bone Adjunctive therapy with hyperbaric oxygen (HBO) in combi-
metastases, because these patients are at risk for the develop- nation with surgery has been investigated(270,271) with encour-
ment or advancement of bone malignancies and teriparatide aging results. Further research is required with these innovative
should be avoided unless prospective studies demonstrate a combination therapies prior to formalizing treatment
favorable benet-to-risk ratio for its use. recommendations.
Other experimental treatment approaches found in the In summary, in the absence of debilitating ONJ lesions,
literature awaiting further substantiation include topically conservative therapy with optimal oral hygiene, topical
applied ozone,(257) bone marrow stem cell intralesional antibiotic rinses, and systemic antibiotics are advised as needed
transplantation,(258) and addition of pentoxifylline and tocoph- for pain or infection.(238)
erol to the standard antibiotic regimen.(259) The latter reportedly For nonresponsive ONJ lesions, surgery is an option and
reduced both ONJ symptoms and the amount of exposed bone. includes ostectomy of the affected area with resection margins
One in vitro study suggested that geranylgeraniol might that extend into adjacent normal-appearing bone. Soft tissue
potentially prevent BP-induced predisposition to ONJ.(260) closure should be tension-free with no underlying sharp edges
Favorable outcomes have been reported with low-level laser of bone that could lead to mucosal breakdown.
therapy, in conjunction with conservative and/or surgical In the presence of a pathologic fracture or ONJ extending to
debridement, but further conrmation is needed.(261,262) the sinus or inferior border of the mandible, or if the ostectomy
Conservative therapy should be continued as long as there is to healthy tissue leads to a discontinuity defect, consideration
not: (1) obvious progression of disease; (2) pain that is not being should be given to microvascular composite tissue grafting at
controlled by conservative means; or (3) a patient who has had the time of surgical resection in the mandible and the same or
antiresorptive therapy discontinued by their oncologist because obturator construction for the maxilla.
of ONJ. At present, other adjunctive procedures as discussed in this
section may be considered, but all require further research to
dene their value.
Surgical management
Early treatment recommendations for ONJ discouraged surgical 9. Research and future directions
intervention with conservative therapy continuing indenitely
or until there was progression of disease. However, there are It has been 10 years since the original case descriptions of ONJ
now many reports demonstrating success with surgical were reported. The insights gained during this past decade into
management of these lesions. With surgery, a full-thickness the pathophysiology of ONJ as well as mechanisms involved that
mucoperiosteal ap should be elevated and extended to reveal could be targeted for therapeutic approaches have increased,
the entire area of exposed bone and beyond to disease-free but are not at a sufcient level to enable the development of
margins. Resection of the affected bone should be extended optimal care strategies for our patients.(272) Over these 10 years,
horizontally and inferiorly to reach healthy-appearing, bleeding the paucity of scientically sound information has often led to
bone. Sharp edges should be smoothed and primary soft tissue confusion among patients and healthcare providers. We need to
closure achieved in a tension-free fashion with sutures that do better and must rely on the scientic community, supported
resorb after 1 week.(263) Several authors have reported better by governmental agencies, pharmaceutical companies, and
outcomes with larger resections compared to limited debride- foundations, to expand our knowledge and improve patient
ment and/or conservative therapy.(264,265) care.
Journal of Bone and Mineral Research OSTEONECROSIS OF THE JAW: REPORT FROM THE INTERNATIONAL ONJ TASK FORCE 13
Diagnosis Disclosures
This condition presents as a variably painful ulceration, usually
M Bhandari received funding from Smith and Nephew,
involving the posterior lingual mandible at the level of the
Stryker, Amgen, Zimmer, Moximed, Bioventus, Merck, Eli
mylohyoid ridge.(57,292) There is a hard insensitive base formed
Lilly, Sano, De Puy; ML Brandi has served on the board for
by exposed non-vital bone. The ulcer can persist for periods that
Alexion, Servier, Eli Lilly, and Amgen, and received funding
vary between a few days to several months. Occlusal radio-
from Servier, NPS, Eli Lilly, Amgen, Alexion, Shire, SPA, Bruno
graphs show a localized radiopacity, representing the necrotic
Farmaceutici, and MSD; J Brown has served on the board for
bone, supercial to the lingual cortical plate. Similar lesions can
Amgen, Eli Lilly, and Merck, and received funding for grant,
occur over oral exostoses. Histopathologic exam of the necrotic
lectures, and development of educational presentations from
bone base shows irregular zones of resorption, microbial
Amgen, Eli Lilly, Merck, Novartis, and Actavis; A Cheung
colonization, and often, adherent fragments of acutely inamed
received grants and consultancy fee from Amgen, Eli Lilly, and
granulation tissue. The condition occurs in the absence of
Merck, and honoraria from Amgen and Eli Lilly; C Cooper
predisposing systemic disease or antiresorptive therapy.
received consultancy, lecture fees, and honoraria from
Pathophysiology Amgen, GSK, Alliance for Better Bone Health, MSD, Eli Lilly,
Pzer, Novartis, Servier, Merck, Medtronic, and Roche; D
The pathogenesis is not well understood. However, ulceration, Hanley received fees for consultancy, lectures, development
either traumatic or in the form of an aphthous ulcer, is thought of educational presentations from Amgen, Eli Lilly, Merck,
to be the initial pathologic event.(57,292) Sequestration could Novartis, and Warner Chilcott; R Eastell received grants,
occur following subsequent disruption of blood supply from the lecture fees, and travel expenses from Amgen, AstraZeneca,
periosteal layer to the poorly vascularized supercial cortical IDS, Novartis, Roche, Alexion, Otsuka, IBMS, and Merck; K
bone and possible secondary infection. The devitalized and Davison has served on the board for Amgen Merck and
secondarily infected bone base then impedes resolution of the Novartis and received consultancy, lecture fees, funding for
ulcer. The predilection of the condition for posterior lingual development of educational presentations, and manuscript
mandibular bone has resulted in suggestions that the anatomic preparation and travel expenses from Amgen, Merck, and
site might be of etiologic importance. Of possible signicance, Novartis; T Guise has received consultancy, expert testimony
many of these cases occur in patients who have lost posterior lecture fees from Novartis, AstraZeneca, Amgen, and Exelixis;
molars or have restorations, which do not recapitulate the L McCauley received consultancy fees from Dentsply and
normal lingual inclination of the molars. Thus, the protective owns Amgen stock; B Josse has served on the board for
lingual inclination of the molars over the mylohyoid ridge is lost Merck, Eli Lilly, and Amgen, and received funding for grants,
and the nonkeratinized mucosal lining over the projecting lectures, and travels from Amgen and Eli Lilly; D Kendler
mylohyoid ridge would not be shielded from chronic trauma received consultancy, grants, and lecture fees from Amgen,
during mastication. After the ulcer has formed, it would be Pzer, Eli Lilly, Merck, and Astellas; A Khan has served on the
further susceptible to secondary infection because it is located in board for Amgen and Eli Lilly and has received grants and
a relatively stagnant oral region. The suggestion that an lecture fees from Amgen, Eli Lilly, NPS, and Merck; B Langdhal
aphthous ulcer, rather than a traumatic ulcer, might be the has served on the board for Amgen, Merck, and Eli Lilly, and
primary lesion could result in the same sequence of pathologic received consultancy fees and grants from Eli Lilly, Axellus,
events, and these are not mutually exclusionary suggestions. Amgen, Merck, and Eli Lilly; S Morin has served on the board
for Amgen, Merck, and Eli Lilly, and received consultancy fees
Management and grants from Merck; B Obermayer-Pietsch received
This is usually a self-limited condition that heals with conserva- consultancy and lecture fees from MSD, IDS, and Eli Lilly; F
tive measures.(57,292) The necrotic bone may undergo sponta- ORyan received support for travel from AAOMS; E Peters no
neous exfoliation. If the sequestrum is mobile, the process can conict to disclose. I Ried has served on the board for Merck,
be expedited with gentle manipulation of the sequestrum and received consultancy, testimony, and lecture fees from
through the ulcer base. If the dead bone is adherent to the Novartis, Merck, Amgen, Sano, and Eli Lilly; S Ruggerio
underlying cortex, surgical removal might be required. However, received consultancy fees from Amgen; D Saunders received
often a patient approach with supportive management consultancy fees from Takeda; A Taguchi received consultan-
involving antimicrobial rinses, such as chlorhexidine or tetracy- cy and lectures fees and grants from Asahi Kasei and Teijin; S
cline, will result in detachment of the sequestrum from Tetradis has received consultancy fees and grants from
underlying vital bone and eventually permit spontaneous Amgen; N Watts is the co-founder, director, and stockholder
exfoliation. Once the necrotic bone has been removed, efcient of OsteoDynamics, and has received consultancy and lecture
healing occurs.(299) fees from Amgen, AbbVie, Amarin, Bristol-Meyers Squibb,
Corcept, Endo, Imagepace, Janssen, Eli Lilly, Merck, Novartis,
Future research directives Noven, NPS, Pzer/Wyeth, Radius, and Sano-Aventis;
J Compston, B Masri, A Morrison, D Pierroz, E Rabbany, and
There is a need for further research on OUBS. Studies are G Sndor state that they have no conicts of interest.
required to evaluate the incidence and prevalence of this
condition. The proportion of OUBS conditions that can result in
signicant morbidity in terms of size, duration, and pain should Acknowledgments
be assessed. Development of a staging system would be of
value, particularly with respect to optimization of treatment Expert Panel of Reviewers: Howard Holmes, Edward Dore, Maria
strategies. The role of this condition as an initiating event for the Luisa Bianchi, Michel Fortier, Michel Fortin, Kevin Lung, Douglas
signicant drug-associated ONJs should be evaluated. Peterson, Reena Talwar, and Toshiyuki Yoneda.
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